Study of FBN1 gene expression in animal models for Marfan Syndrome

• Grant number: 06/00120-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: April 01, 2006
• End date: March 31, 2007
• Field of knowledge: Biological Sciences - Genetics
• Principal Investigator: Lygia da Veiga Pereira
• Grantee: Gustavo Ribeiro Fernandes
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Marfan syndrome (MFS) is the most common, autossomal-dominant, systemic disorder of connective tissue (OMIM# 154700), with an estimated prevalence of 1 in 10.000 individuals. Despite the fact MFS has a large range of clinic manifestation inter and intra-families, it´s a completely penetrant phenotype and main manifestations involves the skeletal, ocular and cardiovascular systems. Was shown that mutations in the gene for fibrilin-1 (FBN1) leads to the appearance of MFS, fibrilin-1 is the principal structural component in the microfribrils that exist in the extracellular matrix, and together with elastin are responsible for the formation of the elastic fibre. It´s though that MFS follows the dominant-negative model, which say that the “mutant” fibrilin interact with the “normal” fibrilin, and by doing so they interfere the correct organization and integrity of the microfibrils. However, recent studies give rise to the possibility that MFS is caused by the haploinsufficiency of “normal” fibrilin-1, using other words, mutations in the gene FBN1 reduce the production of the “normal” protein and consequently the microbibrils that is form lacks in resistance and can´t give the appropriated support to tissues. To create an animal model capable of simulate the dominant-negative effect in MFS, mices (Mus musculus) had the Fbn1 gene modified by homolog recombination in stem cells to generate the model mgΔloxPneo. This mutation was transfer to two different isogenic background, C57Bl/J6 and 129/Sv. Heterozygotes animals from the latter background present skeletal deformities similar to MFS with some variability (change of skeletal structure in different levels of severity), while in the former background heterozygotes animals to do not show any clinic manifestation of MFS. The objective of this work is verify whether exist some correlation between the severity of the disease manifestation in heterozygotes animals from the two isogenic background and the different levels of expression of both fibrilins.